Hepatitis C virus (HCV) is an important cause of chronic liver disease, cirrhosis and hepatocellular carcinoma in many parts of the world. Its fastidious mature and limited host range have made it difficult to study. In this program, four separate groups of investigators join forces to attack the hepatitis C virus from a variety of different but interrelated vantage points. The groups have a well documented history of prior collaborations in the general area of hepatitis viruses and bring a broad assortment of talents and interests to this program. The projects will emphasize studies on HCV pathogenesis and immunity and will range from clinically based investigation to fundamental analysis of the HCV genome. By combining resources, reagents and ideas, the program team hopes to advance the state of knowledge concerning HCV pathogenesis. The individual projects in this program are briefly outlined. Dr. Greenberg, who is the overall program director, will carry out studies on the viral and cellular factors that regulate the early events of binding and entry of HCV into target cells. These studies will shed light on important aspects of host range restriction and tissue tropism and will have considerable relevance to the studies of Drs. Rice and Wright. Dr. Rice will carry out basic investigations of a newly identified nucleic acid sequence in the HCV genome located at the 3' end. He will try to determine if the presence or quantity of genomes containing this sequence is correlated with certain clinical factors or with HCV infectivity. He will also utilize his new "full length" genomes to produce infectious RNA. An infectious HCV clone would greatly aid the studies of Dr. Greenberg. Such studies are critical to our understanding of persistence, immunity and clinical course.